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New muscular dystrophy drug trialled

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The BBC reported that a new study has provided “hope for Duchenne muscular dystrophy”.

Duchenne muscular dystrophy is a progressive condition caused by mutations within a person’s DNA that prevent their body from producing the regular form of a protein called dystrophin. This protein forms vital connections in the muscle tissue, and without it the muscles degenerate, shortening a person’s lifespan.

In this study, UK researchers trialled a new drug designed to make the body bypass genetic mutations when producing dystrophin. When given to 19 children with Duchenne muscular dystrophy, researchers found that higher doses of the drug, known as AVI-4658, led to an increase in dystrophin.

Researchers believe that drugs which are designed to make the body “skip over” mutations in this way could be used to treat approximately 83% of Duchenne muscular dystrophy cases. However, the drug used in this trial only targeted mutations in a region implicated in 13% of cases.

This study was conducted well and demonstrated the potential of this approach for increasing the levels of dystrophin in the short term. The trial’s principal aim was to work out the appropriate dosages of the drug, therefore the drug’s safety profile and effects will need to be confirmed in larger, longer-term studies, particularly as patients would need to take it for the rest of their lives.

Where did the story come from?

The study was carried out by researchers from University College London Institute of Child Health and several other UK universities and hospitals. It was funded by the UK Medical Research Council and AVI BioPharma, the manufacturer of the drug being tested. The study was published in peer-reviewed medical journal The Lancet.

The BBC covered this story well.

What kind of research was this?

Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations affecting the production of a protein called dystrophin. Dystrophin is important in the formation of structures within muscle fibre, but people who have problems producing dystrophin due to DMD experience progressive muscle weakness and muscle wasting. Due to the way the condition is inherited, DMD mainly affects males, being found in one in 3,500 newborn boys. Many patients with the disease lose the ability to walk by the age of 11, and have a shorter life expectancy. There is currently no cure for DMD.

The primary aim of this study was to assess the safety and tolerability of a new drug, AVI-4658, at a range of increasing doses in patients with Duchenne muscular dystrophy aged between 5 and 15 who could still walk. The secondary aim of this trial was to assess the ability of this drug to restore levels of the dystrophin protein.

To explore these aims, researchers conducted an open-label (non-blinded), phase 2, dose-escalation study. This is the appropriate trial design to answer this question. However, larger, long-term trials will be required to confirm the findings from this trial, and to determine whether treatment with this drug can cause clinically significant improvements, particularly improvements that can be sustained in the long-term.

What did the research involve?

In Duchenne muscular dystrophy, patients have genetic mutations which interfere with the production of the protein dystrophin, causing a non-functional version of the protein to be produced. This is because these mutations cause abnormalities in the DNA sequence that the body would use as a blueprint for making dystrophin. In this study, the researchers used a drug called AVI-4658 to encourage the cellular machinery to “skip” over the genetic region containing the mutation, allowing a shortened but functional version of the protein to be produced. This technique has already been shown to work in a laboratory setting and in animal models.

The researchers recruited nineteen patients aged between 5 and 15 with Duchenne muscular dystrophy caused by a mutation in a particular region of the DMD gene (called exon 51). These patients could still walk. They were given weekly intravenous infusions of the drug (AVI-4658) for 12 weeks. The study tested a range of drug doses, ranging from 0.5mg per kg of body weight up to 20mg per kg of body weight. Three to four patients received each dose. Participants had a small muscle sample (biopsy) taken before starting treatment and after the 12 weeks of treatment so that researchers could examine how muscle tissue changed in response to treatment.

The levels of the dystrophin protein that treatment produced and the drug’s ability to cause “skipping” over the region with the mutation were assessed.

What were the basic results?

The drug, AVI-4658, was tolerated well, with no serious adverse drug-related events. AVI-4658 induced “skipping” over the region with the mutation in all participants, and seven patients had a post-treatment increase in dystrophin protein levels in their muscle. The level of dystrophin protein produced generally increased the higher dose of the drug, with a dose of 2mg/kg being the lowest dose to produce an effect on dystrophin levels.

The researchers also confirmed that the dystrophin protein produced appeared to be working properly, as the muscle fibres producing dystrophin also had increased levels of other proteins, which normally bind to dystrophin. Some of the participants treated with higher doses of the drug also showed a reduction in immune system cells that are normally seen in the muscle of DMD patients.

How did the researchers interpret the results?

The researchers concluded that the safety and efficacy [effectiveness under test conditions] seen in this research “show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy”.


This was a well-performed study that has demonstrated the potential of this approach for increasing the levels of dystrophin in boys with DMD. However, it is important to note that this was a small, short-term study primarily aimed at helping to set the appropriate dosage for the drug rather than establishing its effectiveness. The safety profile and effects of the drug will now need to be confirmed in larger, longer-term clinical trials, particularly as this drug would have to be given to patients for the rest of their life. It would also be crucial to determine whether the biological improvements seen in muscle tissue translate into significant clinical improvement in patients’ symptoms.

Duchenne muscular dystrophy can be caused by different mutations in the dystrophin gene. It is thought that “skipping” regions containing mutations could treat around 83% of the genetic errors causing Duchenne muscular dystrophy. However, different drugs would have to be developed to target mutations in different regions. This drug targets mutations in exon 51, which occur in 13% of boys with Duchenne muscular dystrophy.

That said, this initial set of results shows some promise, and if the drug can perform well in future trials then it may become a viable option for treating a this debilitating, life-limiting disease.


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